Arnout R. Alberts

Compliance Rates with the Prostate Cancer Research International Active Surveillance (PRIAS) Protocol and Disease Reclassification in Noncompliers

BACKGROUND Men with prostate cancer on active surveillance (AS) are advised to follow strict follow-up schedules and switch to definitive treatment on risk reclassification. However, some men might not adhere to these strict protocols. OBJECTIVE To determine the number of noncompliers and disease reclassification rates in men not complying with the follow-up protocol of the Prostate Cancer Research International Active Surveillance (PRIAS) study. DESIGN, SETTING, AND PARTICIPANTS A total of 4547 men with low-risk prostate cancer were included and prospectively followed on AS. Men were regularly examined using prostate-specific antigen (PSA), digital rectal examination, and repeat biopsies, and were advised to switch to definitive treatment on disease reclassification (>cT2c, Gleason score > 3+3, >2 cores positive, or PSA doubling time [PSA-DT] 0-3 yr). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Rates of men not complying with follow-up visits or a recommendation to discontinue AS are reported. Biopsy outcome (Gleason ≥7 or >2 cores positive) was compared between compliers and noncompliers using Cox proportional hazards analysis. RESULTS AND LIMITATIONS The compliance rate for PSA visits was 91%. By contrast, the compliance rate for standard repeat biopsies decreased over time (81%, 60%, 53%, and 33% at 1, 4, 7, and 10 yr after diagnosis, respectively). Yearly repeat biopsies in men with faster rising PSA (PSA-DT 3-10 yr) was low at <30%, although these men had higher upgrading rates at repeat biopsy (25-30% vs 16%). PSA-DT of 0-3 yr was the most common recommendation for discontinuation, but 71% continued on AS. Men with PSA-DT of 0-3 yr were at higher risk of upgrading on repeat biopsy (hazard ratio 2.02, 95% confidence interval 1.36-3.00) compared to men without fast rising PSA. CONCLUSION Some men and their physicians do not comply with AS follow-up protocols. In particular, yearly repeat biopsies in men with fast rising PSA are often ignored, as is the recommendation to discontinue AS because of very fast rising PSA. Although these men are at greater risk of higher Gleason scores on repeat biopsy, the majority still exhibit favorable tumor characteristics. Fast rising PSA should therefore not trigger a recommendation to receive active treatment, but should rather serve as a criterion for stricter follow-up. In addition, we should aim to find ways of safely reducing the number of biopsies to increase adherence to AS protocols. PATIENT SUMMARY We looked at compliance with an active surveillance protocol for low-risk prostate cancer in a large active surveillance study. We observed reluctance to undergo yearly biopsies because of fast rising prostate-specific antigen, despite a higher risk of disease progression. Further research should aim to safely reduce the number of repeat biopsies in men on active surveillance to increase protocol adherence.

Prostate-specific antigen-based prostate cancer screening: Past and future

Prostate‐specific antigen‐based prostate cancer screening remains a controversial topic. Up to now, there is worldwide consensus on the statement that the harms of population‐based screening, mainly as a result of overdiagnosis (the detection of clinically insignificant tumors that would have never caused any symptoms), outweigh the benefits. However, worldwide opportunistic screening takes place on a wide scale. The European Randomized Study of Screening for Prostate Cancer showed a reduction in prostate cancer mortality through prostate‐specific antigen based‐screening. These population‐based data need to be individualized in order to avoid screening in those who cannot benefit and start screening in those who will. For now, lacking a more optimal screening approach, screening should only be started after the process of shared decision‐making. The focus of future research is the reduction of unnecessary testing and overdiagnosis by further research to better biomarkers and the value of the multiparametric magnetic resonance imaging, potentially combined in already existing prostate‐specific antigen‐based multivariate risk prediction models.

Complications after prostate biopsies in men on active surveillance and its effects on receiving further biopsies in the Prostate cancer Research International: Active Surveillance (PRIAS) study

To study the risk of serial prostate biopsies on complications in men on active surveillance (AS) and determine the effect of complications on receiving further biopsies.

Risk-stratification based on magnetic resonance imaging and prostate-specific antigen density may reduce unnecessary follow-up biopsy procedures in men on active surveillance for low-risk prostate cancer

To assess the value of risk‐stratification based on magnetic resonance imaging (MRI) and prostate‐specific antigen density (PSA‐D) in reducing unnecessary biopsies without missing Gleason pattern 4 prostate cancer in men on active surveillance (AS).

Characteristics of Prostate Cancer Found at Fifth Screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: Can We Selectively Detect High-grade Prostate Cancer with Upfront Multivariable Risk Stratification and Magnetic Resonance Imaging?

BACKGROUND The harm of screening (unnecessary biopsies and overdiagnosis) generally outweighs the benefit of reducing prostate cancer (PCa) mortality in men aged ≥70 yr. Patient selection for biopsy using risk stratification and magnetic resonance imaging (MRI) may improve this benefit-to-harm ratio. OBJECTIVE To assess the potential of a risk-based strategy including MRI to selectively identify men aged ≥70 yr with high-grade PCa. DESIGN, SETTING, AND PARTICIPANTS Three hundred and thirty-seven men with prostate-specific antigen ≥3.0 ng/ml at a fifth screening (71-75 yr) in the European Randomized study of Screening for Prostate Cancer Rotterdam were biopsied. One hundred and seventy-nine men received six-core transrectal ultrasound biopsy (TRUS-Bx), while 158 men received MRI, 12-core TRUS-Bx, and fusion TBx in case of Prostate Imaging Reporting and Data System ≥3 lesions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The primary outcome was the overall, low-grade (Gleason Score 3+3) and high-grade (Gleason Score ≥ 3+4) PCa rate. Secondary outcome was the low- and high-grade PCa rate detected by six-core TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx. Tertiary outcome was the reduction of biopsies and low-grade PCa detection by upfront risk stratification with the Rotterdam Prostate Cancer Risk Calculator 4. RESULTS AND LIMITATIONS Fifty-five percent of men were previously biopsied. The overall, low-grade, and high-grade PCa rates in biopsy naïve men were 48%, 27%, and 22%, respectively. In previously biopsied men these PCa rates were 25%, 20%, and 5%. Sextant TRUS-Bx, 12-core TRUS-Bx, and MRI ± TBx had a similar high-grade PCa rate (11%, 12%, and 11%) but a significantly different low-grade PCa rate (17%, 28%, and 7%). Rotterdam Prostate Cancer Risk Calculator 4-based stratification combined with 12-core TRUS-Bx ± MRI-TBx would have avoided 65% of biopsies and 68% of low-grade PCa while detecting an equal percentage of high-grade PCa (83%) compared with a TRUS-Bx all men approach (79%). CONCLUSIONS After four repeated screens and ≥1 previous biopsies in half of men, a significant proportion of men aged ≥70 yr still harbor high-grade PCa. Upfront risk stratification and the combination of MRI and TRUS-Bx would have avoided two-thirds of biopsies and low-grade PCa diagnoses in our cohort, while maintaining the high-grade PCa detection of a TRUS-Bx all men approach. Further studies are needed to verify these results. PATIENT SUMMARY Prostate cancer screening reduces mortality but is accompanied by unnecessary biopsies and overdiagnosis of nonaggressive tumors, especially in repeatedly screened elderly men. To tackle these drawbacks screening should consist of an upfront risk-assessment followed by magnetic resonance imaging and transrectal ultrasound-guided biopsy.

Biopsy undergrading in men with Gleason score 6 and fatal prostate cancer in the European Randomized study of Screening for Prostate Cancer Rotterdam

A total of 15 men who died of prostate cancer had cT1/2 biopsy Gleason score ≤6 prostate cancer at prevalence screening in the European Randomized study of Screening for Prostate Cancer Rotterdam. Our objective was to explain (part of) these prostate cancer deaths by undergrading with the classical Gleason score.

Distribution of PI-RADS Score and Diagnostic Accuracy of MRI-targeted Biopsy: Comparison of an Asian and European Cohort

Background This study aimed to compare the distribution of Prostate Imaging Reporting and Data System (PI-RADS) score and the diagnostic accuracy of magnetic resonance imaging (MRI)–targeted biopsy and systematic biopsy between a Chinese and a Dutch cohort. Materials and methods Our study includes 316 men from Shanghai Changhai Hospital, China, and 266 men from the Erasmus University Medical Center, Rotterdam, the Netherlands. All men had a suspicion for prostate cancer (PCa) and were offered an multiparametric MRI (mpMRI) scan. Results The distribution of the PI-RADS score was different between the two cohorts (P = 0.008). In the Chinese cohort of PI-RADS ≥3, the detection rate for high-grade PCa (Gleason ≥7) was 37.3% by systematic biopsy and 35.5% by MRI-targeted biopsy. The sensitivity of systematic biopsy was 0.80 for PCa and 0.75 for high-grade PCa. MRI-targeted biopsy achieved slightly higher sensitivity for PCa (0.82) and high-grade PCa (0.76). In the Dutch cohort of PI-RADS ≥3, the high-grade PCa detection rate was 44.4% and 54.5% for systematic biopsy and MRI-targeted biopsy. The sensitivity of systematic biopsy was 0.93 for PCa and 0.81 for high-grade PCa. By MRI-targeted biopsy, the sensitivity was 0.85 for PCa and 0.97 for high-grade PCa. Conclusions The distribution of the PI-RADS score was different with more PI-RADS 4/5 in the Chinese cohort. Applying a PI-RADS ≥3 cutoff resulted in a favorable overall sensitivity. MRI-targeted biopsy showed a higher sensitivity in the detection of high-grade PCa than systematic biopsy. The sensitivity of MRI-targeted biopsy and systematic biopsy for both PCa and high-grade PCa in the Dutch cohort was superior to those in the Chinese cohort.

Editorial Comment to Prognostic factors of prostate cancer mortality in a Finnish randomized screening trial

In this issue of the International Journal of Urology, Neupane et al. present their study on prognostic factors of prostate cancer mortality in the Finnish randomized study of screening for prostate cancer. The authors should be applauded for their excellent analyses of a cohort of nearly 8000 prostate cancer patients with a median follow-up period of no less than 16 years. The prediction of prostate cancer mortality at diagnosis is of the utmost importance, as it should guide the decision for a specific treatment strategy, which could be active treatment with curative intent, active surveillance, watchful waiting or palliative treatment. Neupane et al. showed large effects of PSA, Gleason score and prognostic risk group on the prostate cancer mortality, and only small effects of age and comorbidity. This could give the false impression that one should only look at tumorrelated characteristics rather than taking into account the patient-related characteristics when predicting the prostate cancer mortality. However, one should keep in mind that the majority of patients with prostate cancer still die from other causes. Just 9% (734/7948) of prostate cancer patients in the Finnish trial died of the disease at a median follow-up of 16 years, underlining the importance of age and comorbidity in the prediction of prostate cancer mortality. Within the Finnish trial, no men were screened above the age of 71 years. The age-standardized prevalence of any comorbidity according to the modified Charlson Comorbidity Index was just 9% in prostate cancer patients in the screening arm and 11% in the control arm, respectively. Unfortunately, daily clinical practice is substantially different: wide-scale opportunistic screening of men with little or no chance of benefit of screening based on their age and comorbidities is ongoing, especially in the Western world. Screening of these men has a substantial effect on their quality of life. Thus, age and comorbidity should be taken into account before the decision to screen or not to screen, and as such avoid diagnoses that can only cause harm. After the prostate cancer diagnosis has been made, age and comorbidity might actually be of more importance than the PSA level and Gleason score when choosing a treatment strategy. Unfortunately, we are currently still unable to accurately predict prostate cancer mortality in the long term, even with the combination of tumor-related and patient-related characteristics.

Prediction of High-grade Prostate Cancer Following Multiparametric Magnetic Resonance Imaging: Improving the Rotterdam European Randomized Study of Screening for Prostate Cancer Risk Calculators

BACKGROUND The Rotterdam European Randomized Study of Screening for Prostate Cancer risk calculators (ERSPC-RCs) help to avoid unnecessary transrectal ultrasound-guided systematic biopsies (TRUS-Bx). Multivariable risk stratification could also avoid unnecessary biopsies following multiparametric magnetic resonance imaging (mpMRI). OBJECTIVE To construct MRI-ERSPC-RCs for the prediction of any- and high-grade (Gleason score ≥3 + 4) prostate cancer (PCa) in 12-core TRUS-Bx±MRI-targeted biopsy (MRI-TBx) by adding Prostate Imaging Reporting and Data System (PI-RADS) and age as parameters to the ERSPC-RC3 (biopsy-naïve men) and ERSPC-RC4 (previously biopsied men). DESIGN, SETTING, AND PARTICIPANTS A total of 961 men received mpMRI and 12-core TRUS-Bx±MRI-TBx (in case of PI-RADS ≥3) in five institutions. Data of 504 biopsy-naïve and 457 previously biopsied men were used to adjust the ERSPC-RC3 and ERSPC-RC4. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Logistic regression models were constructed. The areas under the curve (AUCs) of the original ERSPC-RCs and MRI-ERSPC-RCs (including PI-RADS and age) for any- and high-grade PCa were compared. Decision curve analysis was performed to assess the clinical utility of the MRI-ERSPC-RCs. RESULTS AND LIMITATIONS MRI-ERSPC-RC3 had a significantly higher AUC for high-grade PCa compared with the ERSPC-RC3: 0.84 (95% confidence interval [CI] 0.81-0.88) versus 0.76 (95% CI 0.71-0.80, p<0.01). Similarly, MRI-ERSPC-RC4 had a higher AUC for high-grade PCa compared with the ERSPC-RC4: 0.85 (95% CI 0.81-0.89) versus 0.74 (95% CI 0.69-0.79, p<0.01). Unlike for the MRI-ERSPC-RC3, decision curve analysis showed clear net benefit of the MRI-ERSPC-RC4 at a high-grade PCa risk threshold of ≥5%. Using a ≥10% high-grade PCa risk threshold to biopsy for the MRI-ERSPC-RC4, 36% biopsies are saved, missing low- and high-grade PCa, respectively, in 15% and 4% of men who are not biopsied. CONCLUSIONS We adjusted the ERSPC-RCs for the prediction of any- and high-grade PCa in 12-core TRUS-Bx±MRI-TBx. Although the ability of the MRI-ERSPC-RC3 for biopsy-naïve men to avoid biopsies remains questionable, application of the MRI-ERSPC-RC4 in previously biopsied men in our cohort would have avoided 36% of biopsies, missing high-grade PCa in 4% of men who would not have received a biopsy. PATIENT SUMMARY We have constructed magnetic resonance imaging-based Rotterdam European Randomized study of Screening for Prostate Cancer (MRI-ERSPC) risk calculators for prostate cancer prediction in transrectal ultrasound-guided biopsy and MRI-targeted biopsy by incorporating age and Prostate Imaging Reporting and Data System score into the original ERSPC risk calculators. The MRI-ERSPC risk calculator for previously biopsied men could be used to avoid one-third of biopsies following MRI.

MP33-01 SIMILAR HIGH-GRADE PROSTATE CANCER DETECTION BY SEXTANT BIOPSY, 12-CORE TRUS BIOPSY AND MRI-TARGETED BIOPSY IN THE 5TH SCREENING ROUND OF THE ERSPC ROTTERDAM

INTRODUCTION AND OBJECTIVES: In a clinical setting, 12-core TRUS biopsy (12-TRUS-Bx) instead of sextant biopsy (6-TRUS-Bx) increases the low-grade (LG; Gleason 3+3) and highgrade (HG; Gleason >1⁄43+4) prostate cancer (PCa) detection. MRI +/target biopsy (TBx) detects less LG PCa and tends to detect more HG PCa, especially after previous negative biopsy. In this study we compare the performance of 6-TRUS-Bx vs 12-TRUS-Bx vs MRI +/TBx in a pre-screened population-based cohort. METHODS: Men in the 5th screening round of the ERSPC Rotterdam (2013 e 2016) with PSA >1⁄43.0 ng/ml received 6-TRUS-Bx or were included in the MRI side study. Men in the side study received MRI, blinded 12-TRUS-Bx and afterwards fusion target biopsy of PIRADS >1⁄43 lesions if present. The PCa detection rates of the 6-TRUSBx vs 12-TRUS-Bx vs MRI +/TBx strategy were compared after stratification for previous biopsy. RESULTS: A total of 177 men received 6-TRUS-Bx; 158 men received MRI with 12-TRUS-Bx +/TBx. Mean age and mean PSA were resp. 73.2 yrs (SD 1.1) and 5.1 ng/ml (SD 2.8). A total of 78/177 (44%) men who received 6-TRUS-Bx and 74/158 (47%) men who received 12TRUS-Bx +/TBx were biopsy naive. The rate of men with a non-suspicious MRI in the side study was 110/158 (70%).The HG PCa detection rates of 6-TRUS-Bx (17%), 12-TRUS-Bx (20%) and MRI +/TBx (19%) in previously screened but biopsy naive men were comparable. The LG PCa detection rate in biopsy naive men of MRI +/TBx (7%) was significantly lower as compared to 6-TRUS-Bx (23%) and 12-TRUS-Bx (34%). The HG PCa detection rates of 6-TRUS-Bx (5%), 12-TRUS-Bx (5%) and MRI +/TBx (4%) in previously screened and biopsied (>1⁄41 times) men were comparable. The LG PCa detection rate in previously biopsied men of 12-TRUS-Bx (24%) was significantly higher as compared to 6-TRUS-Bx (12%) and MRI +/TBx (7%). CONCLUSIONS: In population-based screening with multiple visits the HG PCa detection rates of 6-TRUS-Bx, 12-TRUS-Bx and MRI +/TBx are comparable, both in biopsy naive and previously biopsied men. Only 5% of previously biopsied men harbor HG PCa at repeat biopsy, confirming the need of better risk-stratification. An MRI +/TBx screening strategy has the potential to reduce biopsy procedures (70%) and overdiagnosis of LG PCa. Source of Funding: none